CN117679525A - Injectable long-acting local anesthetic semisolid gel preparation - Google Patents

Injectable long-acting local anesthetic semisolid gel preparation Download PDF

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CN117679525A
CN117679525A CN202311718969.8A CN202311718969A CN117679525A CN 117679525 A CN117679525 A CN 117679525A CN 202311718969 A CN202311718969 A CN 202311718969A CN 117679525 A CN117679525 A CN 117679525A
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castor oil
gel
pharmaceutical formulation
bupivacaine
solid
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沈惠荣
甘娜
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Huzhou Huizhong Jishi Biotechnology Co ltd
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Huzhou Huizhong Jishi Biotechnology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Abstract

The invention provides injectable long-acting local anesthetic semisolid gel formulations. Specifically, the present invention provides a pharmaceutical formulation comprising: (a) a glyceride mixture comprising: (i) Castor oil, and (ii) a solid glyceride having a melting point between 37 and 75 ℃; wherein the ratio of (i) to (ii) is from 10:1 to 6:3 (w/w); and (B) an active material comprising: (i) Providing a therapeutically effective amount of bupivacaine for at least two days to relieve pain; and, optionally, (ii) a corticosteroid, an analgesic or an anti-inflammatory agent; wherein the active substance is dissolved in the glyceride mixture at a concentration of 0.01-60 wt%; the pharmaceutical formulation is a biocompatible, bioerodible, homogeneous, and monophasic semisolid gel; the viscosity of the pharmaceutical formulation is 50-2000cPs at 30 ℃.

Description

Injectable long-acting local anesthetic semisolid gel preparation
The application is a divisional application of International application No. PCT/US2018/064325, the invention name is 'injectable long-acting local anesthetic semisolid gel preparation', and the application No. 201880079042.5 of the application entering China national stage.
Reference to related patent application
This patent claims priority from U.S. patent application Ser. No. 15/833,899 filed on 6 th 12 th 2017.
Technical Field
The present invention provides a semi-solid pharmaceutical composition for controlled release of a drug comprising a local anesthetic and an anti-inflammatory drug in a semi-solid lipid carrier comprising castor oil and a gelling agent, the pharmaceutical composition controlling the delivery of the local anesthetic in an injectable form for the treatment of postoperative pain.
Background
In the united states, about 1 million surgeries are performed annually, and systemic opioids are used to control postoperative pain, with only half of patients' pain being adequately controlled. Opioid postoperative pain management prescriptions are encouraging opioid abuse because 160 tens of thousands of american surgical outpatients become long-term opioid users each year, 10% of which are addicted to opioids. This terrible situation is a consequence of the non-ideal control of pain that allows opioid prescription and post-operative pain. Furthermore, only 38% of opioids are used at discharge leaving a large number of pills available for abuse and illegal transfer.
To reduce the need for opioids, anesthetics are administered locally by epidural injection, peripheral nerve block or local infiltration. Unfortunately, the duration of action of currently approved anesthetics is less than 12 hours. The most painful is within 24 hours after surgery, requiring powerful analgesic effects to ensure pain relief and opioid sparing. As more outpatient procedures proceed, adequate pain control after discharge is critical.
Compared with bupivacaine aqueous solution, bupivacaine contained in liposomeThe sustained release preparation of (2) provides longer duration of action, and can continuously relieve pain for 24 hours, so that the use of opioid is slightly reduced.
Viscii at 2017,J Am Coll Surg,225 (Supp 2): e37 reports that in phase 2 clinical bunyoctomy studies with HTX-011, the use of a pharmaceutical formulation comprising the anti-inflammatory agents meloxicam and bupivacaine (polyorthoester) for the treatment of postoperative pain, 16% of patients did not require opioid administration to stop pain after bunyoctomy compared to patients with 7% bupivacaine in water alone.
Numerous studies have been conducted by researchers to synthesize hydrolysis-resistant lactic acid-castor oil copolymers for sustained release formulations of bupivacaine. Sokolsky-Papkov in 2009; pharma Res,3:7-10 and 2010,J Pharma Sci,99:2732-38 reports that the addition of bupivacaine to hydrophobic hydrolysis-resistant lactic acid-castor oil copolymer at a concentration of 10% (/ w/v) results in slower degradation rates, prolonged drug release times, and nerve blocks of up to 1-2 days. The biodegradable polymer based on fatty acid releases 60% of bupivacaine within one week and thus no drug burst. A single injection formulation may result in a motor block of 64 hours and a sensory block of 96 hours. However, there is a significant burst of this formulation, leading to systemic toxicity. Increasing bupivacaine concentration to 15% (w/v) can extend the duration of sensory block to 96 hours and exhibit fewer bursts than 10% bupivacaine. This effect is due to the increase in formulation density and hydrophobicity, resulting in a decrease in water penetration into the drug-polymer matrix.
Shikanov at 2007,J Control Release 117:97-103 reported that the addition of 10% (w/v) bupivacaine to an injectable and biodegradable sebacic acid-ricinoleic acid copolymer, showed an extension of sciatic nerve block of 8 to 30 hours. The incorporation of hydrolyzable anhydride linkages in the polymer backbone renders the formulation biodegradable. In vitro experiments, 70% of the drug was released within one week.
Researchers have made a lot of research work in order to develop long-acting slow-release local anesthetics. Drug delivery vehicles are typically composed of a polymeric carrier matrix, through which the drug is degraded and diffused to achieve controlled release. Local anesthetics are typically embedded or encapsulated in microspheres or microparticles and can be applied to the surgical cavity in the form of an implant by injection or infusion. Various publications describe the release profile of local anesthetic formulations prepared using glycerides as a medium, as described below.
Larsen in 2008; drug Develop Indust Pharm,34: measurement of bupivacaine release rates from various oils is disclosed on 297-304. Larsen discloses the use of in vitro tests under non-sink conditions (spin dialysis membrane devices) to simulate drug release following intra-articular injection into the joint cavity. Larsen showed that bupivacaine was useful in fractionating coconut oil (containing C8 and C 10 Mixtures of saturated fatty acids) released 80% in less than two hours. Larsen also discloses that in318PH (with C) 8 And C 10 Triglycerides of mixtures of saturated fatty acids) the release of bupivacaine is comparable to that of coconut oil. Larsen discloses a history of parenteral administration, castor oil is believed to be from an oil solutionPreferred excipients for drug release. Larsen also discloses the release rate of naproxen in various oils, including +.>318PH, castor oil,701 alone or in combination with isopropyl myristate (IPM), and +.>742 in combination with IPM, castor oil is slower than other vegetable oils depending on drug release rate, probably due to the hydrogen bond donating ability of the ricinoleic acid hydroxyl group.
Castor oil has been used as a commercial pharmaceutical productA solvent for testosterone (dodecanoate) injection for testosterone replacement therapy for intramuscular (gluteal) administration. O' Hanlon reported in 2013,Lancet,special issue1 (S14) (https:// doi. Org/10.1016/S2213-8587 (13) 70040-8), the U.S. Food and Drug Administration (FDA) found that care had to be taken to avoid intravascular injections because>Inadvertent access to the vascular system may lead to short-term (60 minutes or less) consequences of vascular occlusion and pulmonary oil micro-embolism POME, manifested primarily as cough, but sometimes with other associated symptoms (cited above). Mechanical blockage of the pulmonary vasculature from POME can cause acute transient pulmonary hypertension, leading to a variety of symptoms, ranging from mild cough to circulatory failure. It is speculated that POME is caused by micro-embolization of the pulmonary vasculature by oil droplets, causing respiratory symptoms. Although other medicines also contain castor oil, < - >The volume of the castor oil is relatively larger than other products. Immediate/rapid release/pouring of large amounts of castor oil by IM injection may lead to bloodTube occlusion and potentially short term/transient POME.
Sundberg, WO2011/121082, discloses an aqueous stable pharmaceutical gel composition comprising (a) an effective anesthetic amount of one or more local anesthetics selected from bupivacaine or lidocaine; (b) The amount of monoglycerides or diglycerides, or long chain fatty acids thereof, is from 15 to 70% by weight, and (c) free long chain saturated or unsaturated fatty acids, and/or (d) one or more solubilisers consisting of polysorbates, sorbitan fatty acid esters, glycerol formal or polyoxyethylated castor oil, in an amount of from 0 to 30% by weight. These compositions are intended for topical administration and are supported by the results of in vitro mucoadhesion tests.
Richlin in US 7,666,914 discloses a composition for topical controlled release comprising an local anesthetic selected from bupivacaine or mepivacaine, and an anti-inflammatory agent selected from ketoprofen, meloxicam and naproxen.
While the above systems are of practical value, their manufacturing process is complex and expensive. In addition, these products have a large amount of drug released at the early stage after injection (also referred to as "burst release"), and the kinetics of drug release are also poor and the reproducibility is poor, so that the analgesic effect in animal experiments and human experiments is not ideal nor reliable. Thus, there is a need for a more effective sustained release drug to effectively control post-operative pain, to act rapidly within the first critical 24 hours, and then to extend for 72 hours.
Disclosure of Invention
In one aspect, the invention provides a pharmaceutical composition comprising
Glyceride mixture comprising
(i) Ricinoleic acid triglyceride; and
(ii) A glyceride selected from the group consisting of: (a) C (C) 12 To C 18 A mixture of fatty acid triglycerides with a higher proportion of long chain fatty acids (SUP DM); (b) C (C) 12 To C 18 (G43/01) of glycerides; (c) A mixture of triglycerides, diglycerides or monoglycerides (WIT E85); (d) C (C) 10 To C 18 A mixture of fatty acid triglycerides (SUP D); or (b)Other solid glycerides having a melting point between 37 ℃ and 75 ℃;
wherein the ratio (i): ii) is from 10:1 to 6:3 (w/w);
(B) An active comprising (i) bupivacaine in a therapeutically effective amount to provide an analgesic effect for at least two days; and optionally (ii) a corticosteroid, analgesic or anti-inflammatory agent;
wherein the active substance is dissolved in the glyceride mixture at a concentration of 0.01-60 wt%; wherein the pharmaceutical composition is a semi-solid gel that is biocompatible, bioerodible, homogeneous and monophasic; wherein the pharmaceutical composition consists of a semi-solid gel having a viscosity of 50-2000cPs (centipoise) at 30 ℃.
In one embodiment of the pharmaceutical formulation, the active substance comprises a corticosteroid, an analgesic or an anti-inflammatory agent, wherein preferably the corticosteroid is a glucocorticoid; alternatively, wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-1 inhibitors and COX-2 inhibitors.
In another embodiment, the glyceride mixture comprises SUP DM, wherein preferably the glyceride mixture comprises castor oil in a ratio of SUP DM of 8:1.0,8:1.1,8:1.2,8:1.3,8:1.4,8:1.5,8:1.6,8:1.7,8:1.8,8:1.9,8:2.0,8:2.1,8:2.2,8:2.3,8:2.4,8:2.5 (w: w).
In another embodiment, less than 80% of bupivacaine is released from the semi-solid gel within 5 days when tested in vitro at 37 ℃.
In another embodiment, the viscosity is less than 701cPs at 30 ℃.
In another embodiment, the pharmaceutical composition releases bupivacaine for at least one week when tested in vitro at 37 ℃.
In another embodiment, the pharmaceutical composition releases bupivacaine for at least two weeks when tested in vitro at 37 ℃.
In another embodiment, the glyceride mixture has a water solubility of less than 1mg/ml or less than 0.1mg/ml in a physiological pH buffer at 37 ℃.
In another aspect of the invention, the glyceride mixture comprises (i) castor oil, and the active substance comprises a corticosteroid, an analgesic or an anti-inflammatory agent, wherein preferably the corticosteroid is a glucocorticoid, or wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-1 inhibitors and COX-2 inhibitors. Preferred glyceride mixtures comprise SUP DM and glyceride mixtures comprise 8:1.8 (w: w) triester ricinoleate SUP DM. Preferably, less than 80% of the bupivacaine is released from the semi-solid gel within 5 days when tested in vitro at 37 ℃, the viscosity is less than 701cPs at 30 ℃, the pharmaceutical composition releases bupivacaine for at least one to two weeks when tested in vitro at 37 ℃, and the glyceride mixture has a water solubility of less than 1mg/ml or less than 0.1mg/ml in physiological pH buffer at 37 ℃.
Drawings
Fig. 1 shows the release of bupivacaine from castor oil gel formulations gelled by different levels of SUP DM and SUP D, including:
CO control castor oil/BUP (92/8),
Gel 001SupDM12:CO/SUP DM/BUP(80/12/8),
Gel 002SupDM20:CO/SUP DM/BUP(72/20/8),
gel 003SupDM30:CO/SUP DM/BUP (62/30/8), and
Gel 004SupD:CO/SUP D/BUP(77/15/8)；
all in PBS, pH 7.4,37 ℃.
FIG. 2 shows the release of bupivacaine (bupivacaine) from castor oil gel formulations gelled by WIT E85, G43/01, hydrogenated castor oil, S378 and lanolin: comprising
Gel 005Wit E85:CO/WIT E85/BUP(77/15/8),
Gel 006G4301:CO/G4301/BUP(77/15/8),
Gel 007HCO:CO/HCO/BUP(80/12/8),
Gel 008S378:CO/S378/BUP(52/40/8),and
Gel 009Lan:CO/Lan/BUP(74/18/8)；
All in PBS, pH 7.4,37 ℃.
Figure 3 shows the release of loteprednol (loteprednol) from a castor oil gel formulation gelled by SUP DM. Gel 001Lote, CO/SupDM/loteprednol (77.8/19.5/2.7); PBS, pH 7.4,37 ℃.
Fig. 4 shows the release of latanoprost (latanoprost) from a castor oil gel formulation gelled by SUP DM. Gel 001Lata CO/SUP DM/latanoprost (80/15/5); PBS, pH 7.4,37 ℃.
Figures 5 and 5a show the hot plate delay versus time as a series of sensory function measurements for bupivacaine castor oil gel formulations, including:
CO control castor oil/BUP (92/8),
Gel 001SupDM:CO/SUP DM/BUP(72/20/8),
Gel 002SupD:CO/SUP D/BUP(72/20/8),
gel 003Wit E85:CO/WIT E85/BUP (72/20/8), and
Gel 004G4301:CO/G43/01/BUP(72/20/8)。
the delayed response time of the foot on a 56 ℃ hotplate was recorded to evaluate the effect of blocking the sensory nerve.
Figures 6 and 6a show foot exercise capacity measurements versus time for a series of bupivacaine castor oil gel formulations, including:
CO control castor oil/BUP (92/8),
Gel 001SupDM:CO/SUP DM/BUP(72/20/8),
Gel 002SupD:CO/SUP D/BUP(72/20/8),
gel 003Wit E85:CO/WIT E85/BUP (72/20/8), and
Gel 004G4301:CO/G43/01/BUP(72/20/8)。
foot exercise ability test animals were evaluated for ability to jump and apply weight to the hind legs using 1 to 4 minutes.
FIG. 7 shows the relationship of hot plate delay to time as a series of sensory function measurements for bupivacaine castor oil gel formulations containing anti-inflammatory agents, including
Gel 005SupDM:CO/SUP DM/BUP(80/12/8),
Gel 005SupDM+BetV:CO/SUP DM/BUP/BetV(79.95/12/8/0.05),
Gel 005SupDM+Keto:CO/SUP DM/BUP/Keto(79.85/12/8/0.15),
Gel 006SupDM+Bet:CO/SUP DM/BUP/Bet(71.95/20/8/0.05),
Gel 006SupDM+MP: CO/SUP DM/BUP/MP (71.85/20/8/0.15), and
Gel 006SupDM+TA:CO/SUP DM/BUP/TA(71.85/20/8/0.15)。
the delayed response time of the foot on a 56 ℃ hotplate was recorded to evaluate the effect of blocking the sensory nerve.
Figure 8 shows a series of rat foot exercise capacity measurements of castor oil gel formulations containing bupivacaine as a function of time, including:
Gel 005SupDM:CO/SUP DM/BUP(80/12/8),
Gel 005SupDM+BetV:CO/SUP DM/BUP/BetV(79.95/12/8/0.05),
Gel 005SupDM+Keto:CO/SUP DM/BUP/Keto(79.85/12/8/0.15),
Gel 006SupDM+Bet:CO/SUP DM/BUP/Bet(71.95/20/8/0.05),
Gel 006SupDM+MP:CO/SUP DM/BUP/MP(71.85/20/8/0.15),
Gel 006SupDM+TA:CO/SUP DM/BUP/TA(71.85/20/8/0.15)。
the motor ability test of the rat feet, using 1 to 4 minutes, evaluates the ability of the animals to jump and apply weight to the hind legs.
Detailed Description
Bioerodible semi-solid carrier technical advantages
The formulations described herein provide a prolonged bupivacaine release that allows the drug to reach an effective therapeutic concentration rapidly in the local area for at least 72 hours. The long-term release has the advantage of achieving rapid pain relief and a high level of active drug in the painful area over a long period of time, thus maximizing pain relief and maintaining the analgesic effect 72 hours after surgery.
Animal model studies used in the present invention showed that bupivacaine analgesics were sustained released for up to 72 hours.
Benefits of bioerodible semi-solid carrier technology:
the semisolid formulations described in the present invention do not exhibit significant burst phenomena. In general, controlled release injections are knownThe phenomenon of abrupt release (abrupt release of a large amount of drug immediately after drug injection) is remarkable. In vitro drug release and animal model studies show that injection based on our bioerodible semi-solid carrier technology has less burst release compared with injection produced by the existing controlled release technology on the market. For example, growth hormone powder for injection(rDNA-derived growth hormone for injection) has a very pronounced burst effect, followed by very slow drug release.
The semi-solid carrier technology described in the present invention has drug loading concentration up to 20% and this value is far higher than other controlled release technologies. For example, a long-acting mepivacaine developed using this semi-solid drug delivery technique can only be loaded with 3% by weight of drug because of its low solubility in the carrier. Furthermore, bupivacaine has a solubility in typical vegetable oils of less than 3% by weight. The solubility of bupivacaine in olive oil, corn oil, sesame oil and vegetable oil was determined to be 2.5 wt%, 2.8 wt%, 3.0 wt% and 2.5 wt%, respectively.
The semisolid gel formulations described herein have a very low viscosity, about 10,000mpa.s or less, even 1000mpa.s or less, at 30 ℃. Thus, such formulations can be injected with very small needles (e.g., 21-gauge or 23-gauge needles) with only minor pain (similar to aqueous injections). Furthermore, due to the high drug loading of the semi-solid gel formulations described herein, less volume of drug needs to be injected. The small injection amount and low viscosity make injection more convenient and less painful. Semisolid formulations of polyorthoesters have viscosities of thousands mpa.s at 30 ℃ and are difficult to inject with a 21 gauge needle.
The formulations of the present invention comprise glycerides and natural fatty acids. These compounds are readily degraded by lipases into glycerol and free fatty acids. These compounds are non-toxic and have good biocompatibility in vivo. The formulations described herein are biodegradable, bioerodible, and fully resorbable. In animal experiments, no adverse effect of the semi-solid formulation on wound healing was observed at 2 weeks post-dosing. The site of administration is pink, and the sciatic nerve is also normal, without inflammation, necrosis, ulceration or infection.
The semi-solid gel formulation techniques described herein are easy and inexpensive to produce compared to microspheres and injections based on controlled release of other polymeric drugs. At relatively low elevated temperatures, the active ingredient is very easy to mix with the semi-solid gel carrier component without the need for solvents. Because of the use of solid glycerides (less than 50 ℃) of relatively low melting point (gelling agent), product production can be carried out at about 60 ℃.
Furthermore, the formulations described herein may be administered directly where desired. Because the formulation can provide sustained drug release (days to months), the duration of pharmacological action is increased, which can reduce the frequency of administration. Compared with systemic administration, the preparation has small side effects (due to local administration), and is easy for patients to accept.
Definition of the definition
All technical and scientific terms herein are used according to their conventional definition as they are commonly used and commonly understood by those skilled in the art of drug delivery. The technical terms used in the present invention are described as follows.
"active agent" includes any active agent that acts locally or systemically, and can be administered to a subject by local administration or by subcutaneous, subconjunctival, intradermal, intramuscular, intraocular or intra-articular injection. Examples of such agents include, but are not limited to, anti-infective agents (including antibiotics, antivirals, fungicides such as itraconazole, insect repellents or acaricides), preservatives (e.g., benzalkonium chloride, chlorhexidine gluconate, furacilin or nitrourea), steroids (e.g., estrogens, progestins, androgens, or adrenocorticoids), therapeutic polypeptides (e.g., exenatide, octreotide, insulin, erythropoietin or morphogenic proteins such as bone morphogenic proteins), corticosteroids, analgesics and anti-inflammatory agents (NSAIDs) (e.g., aspirin, ibuprofen), naproxen, ketorolac, indomethacin, meloxicam, COX-1 inhibitors or COX-2 inhibitors), chemotherapeutic agents and anti-neoplastic agents (e.g., paclitaxel, nitrogen mustard, cyclophosphamide, fluorouracil, thioguanine, carmustine, lomustine, melphalan, chlorambucil, streptozotocin, methotrexate, vincristine, bleomycin, vinblastine, vindesine, actinomycin, daunorubicin, doxorubicin or tamoxifen), 5-hydroxytryptophan (serotonin) 3 (5-HT 3) receptor antagonists for the prevention and treatment of nausea and vomiting after chemotherapy (e.g., granisetron, ondansetron or palonosetron), anesthetics (e.g., morphine, pethidine or codeine), antipsychotics including typical antipsychotics (e.g., haloperidol or fluphenazine) and atypical antipsychotics (e.g., risperidone, clozapine, olanzapine or paliperidone), anti-angiogenic agents (e.g., constant, snake venom disintegrin or anti-vascular endothelial growth factor), polysaccharides, vaccines, antigens, DNA and other polynucleotides, antisense oligonucleotides or siRNA.
Abbreviations used: bupivacaine, BUP; betamethasone, BET; betamethasone valerate, betV; ketoprofen, keto; methylprednisolone, MP; triamcinolone acetonide, TA; meloxicam, MELO.
The semi-solid formulations of the present invention may also find application in other topically acting active substances such as astringents, antiperspirant agents, irritants, fermenting agents, foaming agents, sclerosants, caustic, benefit agents, keratolytic agents, sunscreens and various dermatology including hypopigmentation and antipruritics.
The term "semi-solid" is characterized by a substance that is flowable at moderate pressure. More specifically, the viscosity of the semi-solid material is less than 10,000cps (mpa.s) at 30 ℃.
The term "bioerodible" refers to a substance that gradually breaks down, dissolves, hydrolyzes, and/or erodes in situ. In general, the "bioerodible" semi-solid gels described herein are hydrolyzable materials, and bioerodible is primarily by in situ lipolysis or hydrolysis.
The semisolid lipids, solvents or other reagents of the present invention must be "biocompatible"; i.e. cannot cause irritation and necrosis in the environment of use. The environment of use is a fluid environment and may include subcutaneous, subconjunctival, intramuscular, intravascular (high/low flow), intramyocardial, adventitial, intratumoral, or intracerebral portions, wound sites, tight joint spaces, or body cavities of a human or animal.
Castor oil and gelling agent
Castor oil is a preferred triglyceride component of the semisolid formulations of the present invention. Castor oil is a triglyceride in which about 90% of the fatty acid chains are ricinoleic acid esters. Oleic acid and linoleate are other important components. Castor oil has been used as a solvent (emulsifying and dissolving other water insoluble substances) in certain injectable pharmaceutical products, but is widely used in topical formulations (including ophthalmic formulations) due to its emollient effect.
Castor oil is a liquid with a viscosity of about 700cP at 25 ℃. Although it is a relatively viscous vegetable oil, when a drop of castor oil is added to water or PBS at 37 ℃, it immediately breaks up and dissipates at the surface of the aqueous solution, eventually forming small droplets. Therefore, castor oil is unsuitable for use as a slow release agent.
However, once castor oil is converted to hydrogenated castor oil (castor wax), a hard, high melting point (85 to 88 ℃) wax, the castor oil is hydrogenated by the use of a catalyst, and hydrogenated castor wax has been used as an extended release agent in oral and topical pharmaceutical formulations. In oral formulations, hydrogenated castor oil has been used to prepare sustained release tablets and as a capsule lubricant formulation. In topical formulations, it has been used to provide hardness to creams and emulsions.
The experimental results disclosed below using bupivacaine castor oil solution formulations demonstrate that castor oil can only extend the analgesic effect of bupivacaine from about 2 hours to 4 to 6 hours in a clinically relevant pain model (rat sciatic nerve block pain model) due to its relatively high viscosity and relatively slow dissolution of bupivacaine free base in body fluids.
It has surprisingly been found that when solid gelling agents such asWhen DM (SUP DM) is added to castor oil, the castor oil becomes a soft semi-solid gel. When SUP DM is 5%, gelation is very slow at room temperature (flowable at 37 ℃ body temperature). When SUP DM is equal to or higher than 10%, gelation occurs at room temperature. As the amount of SUP DM increases, less time is required to begin gelation. At a level of 20%, the semi-solid gel formed remains a soft gel and can be injected with a 21 gauge needle. When the amount of SUP DM increases to 30%, the semi-solid gel formed becomes a relatively hard gel and is difficult to inject with a 21 gauge needle.
The castor oil gels according to the invention are characterized in that they have the property of changing from a fluid at room temperature to a gel at room temperature and remain in a certain form (well-defined) when the semi-solid gel is placed in water at 37 ℃.
Furthermore, the slow release of castor oil into water may be due to the cohesive action between the castor oil and the gellant and the relatively hydrophobic semi-solid gel structure. The results herein show the kinetics of release of the active drug from a formulation comprising CO. The stable gel formulation ensures that once infused into the human body, the formulation maintains a form of long-acting depot to control the gradual release of the active agent and prevents the rapid release of castor oil into the blood of animals or humans leading to vascular occlusion and potential pulmonary oil micro-embolism (POME). In addition, because of the low viscosity of the resulting soft semi-solid gel formulation (about 350cP at 30 ℃), it can be easily injected with a 21 gauge needle or used for topical delivery.
The gelling agent is a pharmaceutically acceptable material with good compatibility with castor oil. Since castor oil is a mixture of triglycerides, solid or semi-solid glycerides are well compatible with castor oil to form semi-solid gels.
More specifically, suitable gellants may be solid triglycerides of mixed esters, solid partial glycerides of fatty acids, mixtures of triglycerides, diglycerides or monoglycerides, and other castor oil compatible gellants, such as sterol esters lanolin. Because these gellants are similar in structure to castor oil, they are expected to be compatible. Physically, these substances may be in the form of solid or semi-solid lipids, and should also have a low solubility at room temperature, with a water solubility of less than 1mg/mL, preferably less than 0.1mg/mL, in physiological pH buffers at 37 ℃. If the gelling agent is too hydrophilic and water soluble, it will cause burst release of the active drug, which may cause undesirable side effects, especially when the active drug is relatively soluble. If the gelling agent is significantly less soluble than the primary semi-solid lipid, the time it remains in the body will be significantly longer when the active drug and primary semi-solid lipid are fully dissolved and absorbed by the body.
The solid or semi-solid lipids of the present invention, which are well compatible with castor oil and can form semi-solid gel delivery vehicles for active drugs with castor oil, include solid triglycerides of mixed esters, solid partial glycerides of fatty acids, mixtures of triglycerides, diglycerides or monoglycerides, and other compatible castor oil gellants (e.g., sterol ester lanolin) having a melting point below 100 ℃, preferably between 37 ℃ and 75 ℃, more preferably between 37 ℃ and 50 ℃. When the melting point becomes too high, especially at higher concentrations (> 20 wt%) it will cause hardening of the semi-solid gel and affect the injectability of the semi-solid gel formulation.
The solid triglycerides which can be added to castor oil to form a semisolid gel according to the invention include SUP DM, C 12 To C 18 A mixture of triglycerides having a melting point of 42.5 ℃ to 46 ℃;D(SUP D)，C 12 to C 18 A mixture of triglycerides having a melting point of 42 ℃ to 45 ℃; />CM(SUP CM)，C 12 To C 18 A mixture of triglycerides having a melting point of 37.8 ℃ to 39.8 ℃; />378(S378)，C 10 To C 18 Triglycerides of fatty acids with a melting point of 39 ℃ to 42 ℃; and hydrogenated castor oil having a melting point of 85 ℃ to 88 ℃.
The fatty acid solid partial glyceride which can be added into castor oil to form semisolid gel according to the invention comprises C 12 To C 18 GELUCIRE 43/01 (G43/01) glyceride of fatty acid with melting point of 42-45deg.C; GELEOL TM A glycerol monostearate having a melting point of 54 ℃ to 64 ℃; GELUCIRE 39/01 (G39/01) C 12 To C 18 Monoglycerides, diglycerides and mixtures of triglycerides of fatty acids, with a melting point of 37 ℃ to 40 ℃; and888ATO, glyceryl behenate, melting point 65℃to 77 ℃.
The invention relates to a triglyceride, diglyceride or monoglyceride mixture which can be added into castor oil to form semisolid gel, comprisingE85 (WIT E85) with a melting point of 42 ℃ to 44 ℃; and->E76 (WIT E76) with a melting point of 37℃to 39 ℃.
In addition, other gelling agents that are compatible with castor oil, such as sterol ester lanolin having a melting point of 38 ℃ may be added to the castor oil to form a semi-solid gel.
The concentration of gellant added to castor oil may vary. For example, the concentration (wt%) of the gelling agent may be about 8 to 30 wt%, preferably about 10 to 20 wt%.
The castor oil, after mixing with the gelling agent (final delivery vehicle) and then adding the active substance, forms a long-acting depot of a form once injected into the body (37 ℃), and will gradually degrade/erode and dissolve in the body fluid, the semi-solid lipids eventually hydrolyse into natural free glycerol and free fatty acids by a process known as lipolysis by lipases.
Preparation of castor oil semisolid gel formulation
The castor oil semisolid gel formulations containing an active substance according to the invention can be prepared by direct mixing of castor oil and gelling excipients, or by mixing with the semisolid gel matrix already formed. The mechanical mixing process is carried out at a suitable temperature, typically between 60 ℃ and 90 ℃, to completely melt the gelling excipient and castor oil into a solution and dissolve or grind the active drug by any mechanical means to form a clear solution or homogeneous suspension. Vacuum may be applied to avoid air bubbles and nitrogen may be applied to reduce oxidation of the active drug and delivery vehicle components. After obtaining a uniform pharmaceutical composition, the active substance semi-solid gel formulation may be cooled to room temperature.
Semisolid gel composition of local anesthetic
Local anesthetics can cause temporary nerve block and act as local pain relief for surgery, dental surgery, and trauma.
The clinical local anesthetic belongs to one of the following two drugs: amides and esters local anesthetics. Amide local anesthetics include bupivacaine, ropivacaine, levobupivacaine, dibucaine, etidocaine, lidocaine, mepivacaine. The ester local anesthetics include benzocaine, chloroprocaine, cocaine, proparacaine and tetracaine. The local anesthetic may be present as a free base or an acid addition salt, or as a mixture of both. A mixture of two different local anesthetics, or the same local anesthetic is mixed in two different forms (free base or acid addition salt) to achieve the desired pharmacological effect and release rate and duration.
The active substance (free base) can be easily converted into salts with fatty acids and other pharmaceutically acceptable acids. Saturated and unsaturated fatty acids such as lauric acid, myristic acid, palmitic acid and oleic acid are natural fatty acids which can be used. This transformation may increase its compatibility and solubility in the semi-solid carrier. The selected active may be converted to a salt prior to incorporation into the semi-solid carrier or may be added simultaneously to the semi-solid carrier in a 1:1 molar ratio or other molar ratio during preparation of the formulation.
The amount of the active or actives in the composition may vary within a wide range, depending on several factors such as the therapeutically effective amount of the active agent, the time required for the biological or therapeutic effect, and the release profile of the composition. The concentration of the active substance may be in the range of 0.01 to 60 wt%, preferably in the range of 5 to 40 wt%, or more preferably in the range of 5 to 20 wt%.
A corticosteroid, analgesic or anti-inflammatory agent may be added to the local anesthetic semisolid gel formulation, preferably wherein the corticosteroid is a glucocorticoid; alternatively, wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-1 inhibitors and COX-2 inhibitors. The concentration of the anti-inflammatory agent is selected based on the potency of the drug and its clinical dosage. The anti-inflammatory concentration that locally inhibits inflammation may be in the range of about 0.01 to 1 wt%, preferably about 0.03 to 0.5 wt%, or more preferably about 0.03 to 0.15%.
The glyceride mixture comprises castor oil to gellant relative concentrations of 8:1.0,8:1.1,8:1.2,8:1.3,8:1.4,8:1.5,8:1.6,8:1.7,8:1.8,8:1.9,8:2.0,8:2.1,8:2.2,8:2.3,8:2.4,8:2.5 (w: w).
The concentration (wt%) of the gelling agent may be in the range of about 8 to 30 wt%, preferably about 10 to 20 wt%.
In addition, other pharmaceutically acceptable agents such as permeation enhancers may be added, including natural permeation components such as oleic acid, linoleic acid, and synthetic components such as azone, propylene glycol, N-methylpyrrolidone, antioxidants, preservatives, and other inert agents such as coloring or flavoring agents.
The semisolid pharmaceutical gel composition of the semisolid formulation of the present invention has a smooth semisolid gel texture. Thus, the composition may be filled into 21-25 gauge needle syringes for subcutaneous, subconjunctival, intradermal, intramuscular, epidural or intrathecal injection, or may be conveniently applied to sites that have been opened, such as surgical wounds/sites or exposed skin or mucous membranes.
The active substance is released from the composition in a sustained and controlled manner after administration by injection or topical application. The rate of release may be adjusted in different ways to suit the duration of the desired therapeutic effect. For example, the release rate is increased or decreased by using different amounts of low-solubility semi-solid lipids and different amounts of salts of low-solubility active ingredients. The release rate may also be increased or decreased by selecting different modifying excipients or by varying the amount of excipients, or both. In addition, active substances of lower water solubility, for example in their base form, or as complexes with fatty acids, can be used to delay the release of the active substance.
Medical application
The local anesthetic semisolid pharmaceutical compositions described herein may be applied topically to an already open wound, such as skin or mucous membrane, or the pharmaceutical composition may be loaded into a syringe and injected directly into the surgical cavity and various layers within the wound, such as under the peritoneal incision and skin incision. The present pharmaceutical products generally provide for the topical treatment of surgical incisions and deep visceral pain associated with central and major surgery. This pharmaceutical product allows the first three days of pain, which is most debilitating after surgery, to be relieved. Such products are likely to be widely used for management of postoperative pain in moderate/major surgery, such as abdominal, gynecological, thoracic or orthopedic surgery.
Other semisolid gel pharmaceutical formulations
Exemplary compositions of the semi-solid formulations of the present invention and uses thereof include compositions comprising: ophthalmic drugs for the treatment of ocular inflammation, corticosteroids such as loteprednol etabonate; glaucoma drugs such as latanoprost for the treatment of open angle glaucoma or ocular hypertension; anti-angiogenic drugs such as card Bei Dating for the treatment of macular degeneration and retinal angiogenesis; and other compositions for controlled release of ophthalmic drugs into the eye.
The amount of one or more active agents in the compositions of the present invention can vary within wide limits, depending on a number of factors, such as the therapeutically effective amount of the active agent, the duration of the biological or therapeutic effect, and the release profile of the composition. The concentration of active may be about 0.01 to 60 wt%, preferably about 1 to 10 wt%.
The concentration of the primary semi-solid lipid may be from about 1 to 99 wt%, preferably from about 5 to 80 wt%. The concentration of the first modifying auxiliary material may be about 1 to 50 wt%, preferably about 5 to 20 wt%. The concentration of the second gellant may be about 0.1 to 10 wt%, preferably about 0.5 to 5 wt%. In addition, other pharmaceutically acceptable agents, such as antioxidants, preservatives and other inert agents, such as coloring or flavoring agents, may be added.
Background
S701
701 is prepared by transesterification of castor oil with glycerol in the presence of sodium hydroxide. Castor Oil (CO) is a raw material for S701. S701 only elicits a mild/moderate reversible inflammatory response at the site of administration, but does not affect wound healing or scarring in rats, rabbits and dogs.
The present invention finds that the different batches of S701 are inconsistent, i.e. the appearance changes from liquid to partial liquid/partial semi-solid, semi-solid or paste, and that this change affects the physical state and in vitro release of the formulation. For example, if the S701 lot used is a liquid, the in vitro release of the drug is faster.
Castor Oil (CO)
Castor oil is a stable adjuvant in terms of composition and physical properties such as viscosity. Castor oil is an oil solution, not a sustainable "depot". After injection, it can cause vascular occlusion and potential pulmonary microemulsions, especially when large doses (3-5 ml) are used, and the massive and rapid release of castor oil can be an adjunct safety issue.
Gelling agent
It is an object of the present invention to change castor oil to a stable gel to control drug release and also to control castor oil release into surrounding tissues. Another object is to prevent rapid release of the drug and/or burst release of castor oil.
The invention tests for pharmaceutically acceptable gelling agents. Commonly used fatty acid aluminum salts such as aluminum stearate and magnesium stearate are used. Polymers such as carboxymethyl cellulose, polyvinyl alcohol and polyvinylpyrrolidone are also used. Polysaccharides such as natural pectins and starches are commonly used in aqueous systems and are not compatible with CO. Pectin from different sources was found to provide different gelling capacities due to variations in molecular size and chemical composition. As with other natural polymers, the main problem with pectin is non-uniformity of reproducibility between samples, which may lead to poor reproducibility of drug delivery characteristics.
The gelation experiment was performed as follows. The targeted amounts of gellant and castor oil were weighed and transferred into glass vials and sealed. The mixture was heated to about 96 ℃ for about 10 minutes in a water bath and then vortexed for 1 minute. This procedure was repeated three times for a total of 30 minutes to dissolve the gellant in the castor oil. The experiment was performed with three polymers, carboxymethyl cellulose, polyvinyl alcohol and polyvinylpyrrolidone at a concentration of 0.2% (2 mg of polymer was added to 1 g of castor oil, heated and vortexed at 96 ℃ for 30 minutes, they were all insoluble in castor oil.
Experiments were performed with 0.1%, 0.5% and 1% concentrations of aluminum distearate added to castor oil. The results show that after heating and vortexing at 96 ℃ for 30 minutes, the solubility of aluminum distearate in castor oil is less than 0.1%. When cooled to room temperature overnight, no gel formed.
None of the above-described "gellants" tested were soluble in or compatible with castor oil.
The relatively high melting point glycerides were then tested and the time from onset of gelation to complete gelation was recorded, as well as the release of castor oil in water at 37 ℃. In vitro and in vivo studies have shown that formulations comprising relatively high melting glycerides and castor oil provide better control of bupivacaine release and thus improved analgesic effects. Furthermore, castor oil is a triglyceride and exhibits less inflammation than commercial S701, S701 being a mixture of monoglycerides, diglycerides and triglycerides.
The addition of the anti-inflammatory agent can significantly improve the effect.
Bupivacaine semisolid gel formulation
Solubility of bupivacaine in pure castor oil
The solubility of bupivacaine in castor oil is determined by dissolving bupivacaine in castor oil, mixing the components at an elevated temperature of 70-80 ℃ to form a clear solution which forms a clear oil solution when cooled to ambient temperature. From 5% to 20% bupivacaine can be readily dissolved in castor oil.
Amount of SUPDM required to form castor oil gel
The amount of gelling agent required to form a semisolid gel formulation of castor oil containing 8 wt% bupivacaine is determined by mixing the components to form a clear solution at an elevated temperature of 70-80 c and cooling to room temperature to provide a homogeneous translucent or opaque gel formulation. The results in table 1 show that the gelling agent SUP DM can form semi-solid gel formulations that are translucent or opaque in the range of 10% to 30%.
When the gelling agent SUP DM is 5 wt. -%, the gelling takes place very slowly at room temperature (flowable at 37 ℃ body temperature). When SUP DM is equal to or higher than 10 wt%, gelation occurs at 21 ℃. As the amount of SUP DM increases, less time is required to begin gelling. At a level of 20 wt%, the semi-solid gel formed remains a soft gel and can be injected with a 21 gauge needle. When the amount of SUP DM is increased to 30 wt.%, the semi-solid gel formed becomes a relatively hard gel and is difficult to inject with a 21 gauge needle. The results show that 10 to 20 wt% of SUP DM can be used as a gelling agent, forming a bupivacaine semi-solid gel formulation with good injectability.
Table 1: castor oil/gellant ratio study: bupivacaine semisolid gel formulation
The castor oil gel formed is characterized by having the property of changing from a fluid at room temperature to a gel at room temperature and retaining a morphology of the gel when the semi-solid gel is placed in water at 37 ℃. The above semi-solid gel formulation of ricinoleic bupivacaine for the test in water at 37 ℃ was prepared with 15% sup DM.
Furthermore, very slow release of castor oil into water was also observed, possibly due to the cohesive action between castor oil and gellant and the relatively hydrophobic semi-solid gel structure.
Bupivacaine in the range of 5% to 15% can be easily dissolved in a semi-solid lipid mixture of castor oil and SUP DM. Although up to 15% bupivacaine is soluble in the final semi-solid gel formulation mixture, less than 10% is selected to avoid potential drug crystallization during long term storage.
The concentration of bupivacaine is selected based on its effect and clinical dose. The target bupivacaine concentration is 80-130mg/mL, based on the maximum recommended single dose of 400mg bupivacaine hydrochloride (bupivacaine instructions), the dose volume is 3-5mL for a typical surgical opening of 10-15cm length.
Other gelling agents
Other castor oil compatible gelling agents that form a semi-solid gel formulation of bupivacaine were selected using the above experimental methods. Except for SUP DM, C 12 To C 18 Mixtures of triglycerides having a melting point of 42.5 ℃ to 46 ℃, other solid or semi-solid triglycerides includingD(SUP D)，C 12 To C 18 A mixture of triglycerides having a melting point temperature of 42 ℃ to 45 ℃; />CM(SUP CM)，C 12 To C 18 A mixture of triglycerides having a melting point of 37.8 ℃ to 39.8 ℃; />378(S378)，C 10 To C 18 FatTriglycerides of acids with a melting point of 39 ℃ to 42 ℃; and hydrogenated castor oil having a melting point of 85 ℃ to 88 ℃. These were also tested as gelling agents to allow castor oil to form a semi-solid gel formulation in the presence of bupivacaine.
The semi-solid local anesthetic pharmaceutical composition is prepared as follows: the local anesthetic, castor oil and gellant are added to a glass vessel and then heated to about 60 ℃ to 90 ℃ depending on the carrier components used and the nature of the local anesthetic, allowing the semi-solid lipid and gellant to completely melt into a solution, with continuous stirring, allowing the active drug to completely dissolve in the drug delivery vehicle to form a clear solution. After a homogeneous and homogenous pharmaceutical composition is achieved, the local anesthetic semisolid formulation may be naturally cooled to ambient temperature.
Description of the embodiments
The commercial products of table 2 are used herein and products meeting GMP quality and quantity can be purchased.
Table 2: commercial triglyceride mixtures
EXAMPLE 1 SUP D
C 12 To C 18 SUP D mixtures of triglycerides with melting points of 42 ℃ to 45 ℃. The results of the ratio study of castor oil and SUP D are shown in table 3. The target amounts of each component were weighed into glass vials and heated to about 50 ℃. Placed in a 75 ℃ water bath, mixed/vortexed until all components are completely dissolved and a clear solution is formed.
SUP D requires approximately the same time as SUP DM to start and complete gelation because of their similar properties and melting points. About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at a gellant level of 10-20 wt.%, and could be injected with a 21 gauge needle.
Table 3: castor oil and SUP D ratio studies
Sample numbering Castor oil (g) SUP D(g) Bupivacaine (mg)
SUP D F01 1.64 0.20 160
SUP D F02 1.54 0.30 160
SUP D F03 1.44 0.40 160
EXAMPLE 2 SUP CM
C 12 To C 18 The melting point of the SUP CM mixture of triglycerides is 37.8 to 39.8 ℃. The castor oil and SUP CM ratio studies are shown in table 4. The target amounts of each component were weighed into glass vials and heated to about 75 ℃ in a water bath and mixed/vortexed until all The components were completely dissolved and a clear solution was formed.
Since SUP CM has a low melting point, SUP CM requires a longer time to start and complete gelation than SUP DM.
About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at a gellant level of 10-20 wt.%, and could be injected with a 21 gauge needle.
Table 4: castor oil and SUP CM ratio study
Sample numbering Castor oil (g) SUP CM(g) Bupivacaine (mg)
SUP CM F01 1.64 0.20 160
SUP CM F02 1.54 0.30 160
SUP CM F03 1.44 0.40 160
EXAMPLE 3S 378
C 10 To C 18 The S378 mixture of fatty acid triglycerides has a melting point of 39 ℃ to 42 ℃ and is in a semi-solid state. At higher amounts/concentrations, the gelling capacity is lower than in the hard solid state compared to other solid triglycerides. S378 at a level of 40 wt%, it takes about 6 minutes and 30 seconds to begin gelation, but it takes 36 minutes to complete gelation.
The castor oil and S378 ratio study is shown in table 5. The target amounts of each component were weighed into glass vials and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.
About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at 30-50 wt% gellant levels, and could be injected with a 21 gauge needle. At a level of 20 wt%, the formulation was still flowable after cooling to room temperature.
Table 5: castor oil and S378 ratio study
EXAMPLE 4 hydrogenated castor oil
Hydrogenated castor oil solid triglycerides (HCO) have a relatively high melting point of 85 to 88 ℃. Because of its relatively high melting point, the gellant needs to be heated above 88 ℃ to completely melt and mix homogeneously with castor oil to form a semi-solid gel.
The castor oil and hydrogenated castor oil ratio studies are shown in table 6. The target amounts of each component were weighed into glass vials and heated to about 90 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed. About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at a gellant level of 10-15 wt.%, and could be injected with a 21 gauge needle. At a level of 20 wt%, it takes 1 minute and 25 seconds to begin gelation and 5 minutes to complete gelation. The formulation became a relatively hard gel, which was difficult to inject with a 21 gauge needle.
Table 6: research on proportion of castor oil and hydrogenated castor oil
Sample numbering Castor oil (g) Hydrogenated castor oil (g) Bupivacaine (mg)
HCO F01 1.64 0.20 160
HCO F02 1.54 0.30 160
HCO F03 1.44 0.40 160
The solid partial glyceride of fatty acid comprises G43/01, C 8 To C 18 A mixture of triglycerides having a melting point of 42 ℃ to 45 ℃; GELEOL TM A glycerol monostearate having a melting point of 54 ℃ to 64 ℃; COM, glyceryl behenate, melting point 65 ℃ -77 ℃; and G39/01, C 12 To C 18 The mixture of glycerides of fatty acid mono-, di-and triglycerides has a melting point of 37 ℃ to 40 ℃. These were tested as gelling agents to form a semisolid gel formulation of castor oil in the presence of bupivacaine.
EXAMPLE 5G 43/01
C 8 To C 18 The melting point of the mixture of triglycerides G43/01 is 42 to 45 ℃. Castor oil and G43/01 ratio studies are shown in table 7. The target amounts of each component were weighed into glass vials and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.
It took about 8 minutes 30 seconds and 6 minutes 30 seconds to begin gelation, and 15 wt% and 20 wt% G43/01 took 15 minutes and 13 minutes, respectively, to complete gelation.
About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at a gellant level of 10-20 wt.%, and could be injected with a 21 gauge needle.
Table 7: castor oil and G43/01 ratio study
Sample numbering Castor oil (g) G43/01(g) Bupivacaine (mg)
G43/01F01 1.64 0.20 160
G43/01F02 1.54 0.30 160
G43/01F03 1.44 0.40 160
Example 6 COM
Castor oil and COM ratio studies are shown in table 8. The melting point of the solid glyceryl behenate is 65 to 77 ℃. The target amounts of each component were weighed into glass vials and heated to about 80 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.
About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at a gellant level of 10-20 wt.%, and could be injected with a 21 gauge needle. At 10 and 15 wt% levels, a 21 gauge needle may be used for injection. At the 20 wt% level, the formulation became a relatively hard gel and could not be injected with a 21 gauge needle.
Table 8: castor oil and COM ratio studies
Sample numbering Castor oil (g) COM(g) Bupivacaine (mg)
Com F01 1.64 0.20 160
Com F02 1.54 0.30 160
Com F03 1.44 0.40 160
EXAMPLE 7 GEL
Castor oil and GEL ratio studies are shown in table 9. The solid glyceryl monostearate has a melting point of 54 to 64 ℃. The target amounts of each component were weighed into glass vials and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.
About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at a gellant level of 10-20 wt.%, and could be injected with a 21 gauge needle.
Table 9: castor oil and GEL ratio study
Sample numbering Castor oil (g) GEL(g) Bupivacaine (mg)
Gel F01 1.64 0.20 160
Gel F02 1.54 0.30 160
Gel F03 1.44 0.40 160
Example 8 WIT E85 and WIT E76
Mixtures of triglycerides, diglycerides or monoglycerides (e.g., WIT E85, melting point 42 ℃ to 44 ℃ and WIT E76, melting point 37 ℃ to 39 ℃) were tested as gellants to enable castor oil to form semisolid gel formulations in the presence of bupivacaine.
Castor oil and WIT E85 ratio studies are shown in table 10. The target amounts of each component were weighed into glass vials and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.
It takes about 8 minutes 30 seconds and 6 minutes 30 seconds to begin gelation, and about 15 minutes and 13 minutes 30 seconds to complete gelation.
About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at a gellant level of 10-20 wt.%, and could be injected with a 21 gauge needle.
Table 10: castor oil and WIT E85 ratio study
Sample numbering Castor oil (g) WIT E85(g) Bupivacaine (mg)
Wit F01 1.64 0.20 160
Wit F02 1.54 0.30 160
Wit F03 1.44 0.40 160
EXAMPLE 9 Natural sterol esters, lanolin (LAN)
Lanolin is an "ester," similar in structure to "glyceride," and is compatible with the triglyceride castor oil. Its melting point is 38 ℃. Lanolin at 18 wt% level takes about 3 minutes and 30 seconds to begin gelation, but due to its high viscosity, it takes 7 minutes to complete gelation.
The castor oil and lanolin ratio studies are shown in table 11. The target amounts of each component were weighed into glass vials and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.
About 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they exhibited a uniform opaque gel after cooling to room temperature at a gellant level of 10-20 wt.%, and could be injected with a 21 gauge needle.
Table 11: castor oil and lanolin ratio study
Sample numbering Castor oil (g) Lanolin (g) Bupivacaine (mg)
Lan F01 1.64 0.20 160
Lan F02 1.54 0.30 160
Lan F03 1.44 0.40 160
EXAMPLE 10 loteprednol etabonate
Loteprednol etabonate (chloromethyl 17-ethoxycarbonyloxy-11-hydroxy-10, 13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta [ a ] ]Phenanthrene-17-carboxylate)Or->) Loteprednol etabonate in the form of an ester is a corticosteroid for use in ophthalmic applications. Ocular applications of the drug include treatment of ocular inflammation due to allergy (according to prescription information form), as well as chronic keratitis (e.g., adenovirus or Thygeson's keratitis), vernal keratoconjunctivitis, tonsillitis, and episcleritis. The composition has little effect on eye pressure.
Semisolid formulation Gel 001Lote: castor oil/SUP DM/loteprednol (77.8/19.5/2.7), castor oil, SUP DM and drug were weighed into glass vials and the caps were screwed. Heating in a water bath to 90 ℃ to melt the carrier component, dissolving loteprednol etabonate to form a clear solution, and cooling to room temperature to become a semitransparent soft gel.
EXAMPLE 11 latanoprost
LatanoprostFor treating glaucoma or ocular hypertension by lowering intraocular pressure.
Semisolid formulation Gel 001Lata was prepared by weighing castor oil, SUP DM and drug into a glass vial and screwing the cap down: castor oil/SUP DM/latanoprost (80/15/5). Heating to 90 ℃ in a water bath melts the carrier component and dissolves the latanoprost to form a clear solution and becomes a translucent soft gel upon cooling to room temperature.
Example 12 in vitro Release
The following semi-solid local anesthetic compositions were prepared as follows: the local anesthetic, castor oil, and gellant are added together in a glass vessel and then heated to about 70 ℃ to 90 ℃ with continuous agitation to completely melt the gellant into a solution, allowing the active agent to completely dissolve in the delivery vehicle to form a clear solution. After a homogeneous and homogenous pharmaceutical composition is achieved, the local anesthetic semisolid formulation may be naturally cooled to ambient temperature. The semi-solid formulation may become a translucent or opaque gel.
CO control castor oil/bupivacaine (92/8),
gel 001SupDM12 castor oil/SUP DM/bupivacaine (80/12/8),
gel 002SupDM20 castor oil/SUP DM/bupivacaine (72/20/8),
gel 003SupDM30 castor oil/SUP DM/bupivacaine (62/30/8),
gel 004SupD castor oil/SUP D/bupivacaine (77/15/8),
gel 005Wit E85 castor oil/WIT E85/bupivacaine (77/15/8),
gel 006G4301 castor oil/G4301/bupivacaine (77/15/8),
gel 007HCO castor oil/HCO/bupivacaine (80/12/8),
gel 008S378 castor oil/S378/bupivacaine (52/40/8),
gel 009Lan castor oil/lanolin/bupivacaine (74/18/8),
gel 010Azone castor oil/SUP DM/BUP/Azone (77.5/12/8/2.5),
Gel 001Lote castor oil/SUP DM/loteprednol (77.8/19.5/2.7),
gel 001Lata castor oil/SUP DM/latanoprost (80/15/5).
Approximately 50mg of the semi-solid formulation was weighed and packaged in a porous semi-permeable membrane, placed in a glass bottle of 100mL PBS having pH7.4, without agitation, and evaluated for the in vitro release profile of bupivacaine. At various time points, samples were taken and analyzed for bupivacaine content at 220nm by UV-Vis, loteprednol at 277nm by UV-Vis, and latanoprost at 210nm by UV-Vis.
The drug release profiles of all the listed semi-solid compositions are summarized in fig. 1 to 4.
The bupivacaine castor oil gel formulation is applicable to surgical incision sites and provides an effective bupivacaine concentration for up to 72 hours to achieve rapid and sustained pain relief. For conventional 10-15cm length surgical incisions, semi-solid gel formulations are expected to provide effective bupivacaine concentrations in appropriate dosage volumes (up to 3-5 mL), and at the end of sustained release, the semi-solid lipid gel is dissolved/eroded and fully absorbed. Bupivacaine on the surface of the formulation rapidly dissolves to immediately and rapidly relieve local pain when the aqueous medium diffuses into the semi-solid gel. As the aqueous medium permeates into the semisolid lipid gel, the semisolid lipid gradually erodes through surface and bulk erosion and gradually dissolves into the surrounding aqueous medium, and bupivacaine will gradually diffuse out and continue to release into the surrounding aqueous medium for a period of time.
As shown in fig. 1, a bupivacaine castor oil solution formulation containing 8 wt% bupivacaine was used as a control formulation. The ricinoleic bupivacaine oil solution produced more than 20% burst at 4 hours, more than 50% release at 24 hours, and almost 70% release at 48 hours under static conditions (no agitation). After another 10% release from day 2 to day 5, the in vitro release profile flattens out. Note that recovery below 100% is due to filtration loss of bupivacaine during sample preparation and inaccuracy of the UV-Vis method. The relatively poor release kinetics of bupivacaine castor oil formulation still enabled an analgesic effect of about 4-6 hours in the rat sciatic nerve block model due to the relatively high viscosity and relatively slow dissolution of bupivacaine free base into body fluids.
When castor oil gels at 12% -30% by SUP DM or SUP D, only about 5% bupivacaine is released at 4 hours, 16-18% at 24 hours, 27-32% at 48 hours, and 54-58% at 5 days, because both gelling agents are more hydrophobic and the gel reservoir structure is stable, bupivacaine is gradually released into the surrounding aqueous solution.
As shown in FIG. 2, bupivacaine castor oil gel formulations were gelled with WIT E85, G43/01, HCO, S378 or LAN, releasing only about 5% bupivacaine within 4 hours, less than 20% at 24 hours, 29-34% at 48 hours, and 53-61% at day 5. This is because all five gelling agents are hydrophobic substances and can prevent water penetration into the gel and slow the release of bupivacaine. Because of the low melting point of S378 and LAN, the resulting gels are softer and release slightly faster than the caffeine. Likewise, for 5 bupivacaine castor oil gel formulations, bupivacaine is gradually released into the surrounding aqueous medium in a sustained manner over 2-3 weeks.
Fig. 3 shows the release of loteprednol etabonate in a castor oil gel formulation gelled by SUP DM, the loteprednol etabonate release profile being up to 7 days due to the relative good water solubility of loteprednol etabonate.
Fig. 4 shows the release of latanoprost from a castor oil gel formulation gelled by SUP DM. Latanoprost is a very hydrophobic drug that is released only 27% on day 10. Latanoprost is released in a sustained manner in vitro for more than one month.
Controlled release mechanism of the formulations described herein
When a semisolid gel formulation is placed in an aqueous environment, water will diffuse into the semisolid lipid matrix and the active substance on the surface of the formulation will first gradually dissolve into the surrounding aqueous medium. As the aqueous medium permeates into the semi-solid lipid gel, the semi-solid lipid gradually erodes through surface and volume erosion and gradually dissolves into the surrounding aqueous medium, and the active substance will gradually diffuse and release into the surrounding aqueous medium in a sustained manner over a period of time.
Factors affecting drug release rate
The semi-solid gel carrier component and the active substance itself have an effect on the release rate and can be adjusted in a number of ways to achieve the desired duration and therapeutic effect desired.
The release rate of the active substance can be increased or decreased by using different types/levels/contents/ratios of hydrophobic glyceride gelling agents with different water solubilities and/or dissolution rates for semi-solid gel carriers. When the water solubility and dissolution rate of the semi-solid gel decrease, the semi-solid gel takes longer to dissolve and absorb, thus resulting in a longer duration of drug release as long as the active substance has a sufficiently low solubility.
In addition, active substances of lower water solubility, for example in their base form, or complexes with fatty acids, can be used to delay the release of the active substance.
Bupivacaine may be present as the free base or salt, such as bupivacaine hydrochloride, which has been widely marketed under various trade names in commercial products, including MARCAINE TM ,And->Bupivacaine has a hydrochloride solubility of 600mg/mL (BASF MSDS data), whereas bupivacaine in the free base form has only the expected water solubility of 0.0977mg/mL (drug bank data). If it is desired to further reduce the water solubility of bupivacaine, fatty acids and other low solubility acids may be used to convert bupivacaine to salt form.
EXAMPLE 13 viscosity measurement
The purpose of the semi-solid formulation viscosity measurement is to demonstrate that the semi-solid formulations disclosed herein have very low viscosity characteristics and are easy to inject through a 23-21 gauge needle.
The viscosity measurement method comprises the following steps:
the viscosity of the semisolid formulation was measured on a calibrated Brookfield RVDV-IPrime CP model viscometer with a cone spindle CPE-51. First, a semi-solid formulation sample stored in a sealed glass vial becomes a flowing viscous liquid after being heated to about 40-50 ℃ in an oven. Then, about 0.5 gram of sample was weighed and placed in the center of the heated sample cup. Air bubbles are avoided as much as possible. The sample cup was mounted to a viscometer and rotated at a suitable speed to maintain the% torque between 10% and 100% while measuring the viscosity. The viscosity and torque% at the target temperature are recorded. Since these materials exhibit ointment properties at room temperature, the viscosity of the semi-solid formulation is measured at 30 ℃, when the semi-solid formulation can form a flowing viscous liquid under pressure. Centipoise (cP) and millipascal-seconds (mpa.s) are CGS and SI units of viscosity. 1 centipoise (1 cP) =1 millipascal-second (mpa.s). The viscosity of all semisolid formulations was determined at 30 ℃.
Viscosity data
Gel formulation with excellent physicochemical properties-low viscosity
Castor oil is a liquid having a viscosity of about 700cP at 25 ℃ and about 451cP at 30 ℃.
The viscosity number of bupivacaine castor oil gel formulations with and without anti-inflammatory effect exhibited low viscosity characteristics ranging from 161cPs to 701cPs, with most of the formulations being below 400cPs at 30 ℃. The gelling agent has two functions, one is to gel castor oil and the other is to reduce the viscosity of the formulation to improve injectability.
Although these formulations are in gel form, they are easily injectable through a 21 gauge needle, with or without a needle, and a single injection can be easier to inject into the incision site.
Viscosity number of bupivacaine castor oil gel formulation
The viscosity results of bupivacaine castor oil gel formulations with and without anti-inflammatory effect are summarized in table 12. The viscosity of all semisolid formulations was measured at 30 ℃.
Table 12: viscosity results of bupivacaine castor oil gel formulations with and without anti-inflammatory effect
Gel preparation composition (wt%) Viscosity number at 30 ℃ (cP)
CO/SUP DM/BUP(82/10/8) 383
CO/SUP DM/BUP(81/11/8) 376
CO/SUP DM/BUP(80/12/8) 365
CO/SUP DM/BUP/BET(76.95/15/8/0.05) 340
CO/SUP DM/BUP/BetV(76.95/15/8/0.05) 342
CO/SUP DM/BUP/Keto(76.85/15/8/0.15) 345
CO/SUP DM/BUP(72/20/8) 298
CO/SUP DM/BUP/MP(71.85/20/8/0.15) 300
CO/SUP DM/BUP/TA(71.85/20/8/0.15) 301
CO/SUP DM/BUP(62/30/8) 251
CO/SUP D/BUP(77/15/8) 320
CO/SUP D/BUP(72/20/8) 287
CO/WIT E85/BUP(77/15/8) 342
CO/WIT E85/BUP(72/20/8) 325
CO/G43/01/BUP(77/15/8) 352
CO/G43/01/BUP(72/20/8) 300
CO/S378/BUP(52/40/8) 161
CO/Lan/BUP(77/15/8) 701
CO/HCO/BUP(82/10/8) N/A
The CO/HCO/bupivacaine (82/10/8) formulation was not completely melted at 60℃due to the high melting point of the component HCO, and thus its viscosity was not measured.
The viscosity number of bupivacaine castor oil gel formulations with and without anti-inflammatory effect exhibits low viscosity characteristics ranging from 161cPs to 701cPs, most of which are below 400cPs at 30 ℃. All gelling agents other than lanolin are waxy solids and act as lubricants due to the waxy nature of the long alkyl chains of fatty acids to reduce the viscosity of the gel formulation. The active substance bupivacaine can also act as a plasticizer and reduce the viscosity of the gel formulation. The addition of a very small amount of anti-inflammatory agent does not normally affect the viscosity of the gel formulation.
All bupivacaine castor oil gel formulations listed in table 12 with and without anti-inflammatory effect were readily injected with mechanical pressure (shear force) using a 21 gauge needle.
Due to the high melting point of component HCO, the CO/HCO/bupivacaine (82/10/8) formulation did not melt completely at 60℃and its viscosity was not measured. However, the formulation can still be injected with a 21 gauge needle.
Example 14 evaluation of skin reaction
The following bupivacaine castor oil gel formulations with and without anti-inflammatory effect, as well as semi-solid formulations previously developed using S701, were subcutaneously administered to each rat on the back side of the clean shave of the chest.
Semi-solid S701/SUP A/BUP (79/13/8),
semi-solid S701+BetV S701/SUP A/BUP (78.95/13/8/0.05),
Gel DM:CO/SUP DM/BUP(81/11/8),
Gel DM+BetV:CO/SUP DM/BUP/BetV(80.95/11/8/0.05).
data for evaluation of injection site edema/erythema response are presented in table 13.
Table 13: skin response assessment
The injection site edema/erythema results for the test formulations are shown in tables 14 and 15. Due to the semi-solid formulation, animals had obvious palpable masses (edema scores 2 to 3) immediately after injection in all dosing areas. Semi-solid S701 exhibited edema on days 1 and 2 and gradually resolved from day 3 to day 8. Edema was eliminated in the presence of 0.05% betamethasone valerate. Semi-solid S701 also exhibited moderate erythema on days 1 and 2, and gradually resolved from day 3 to day 8. Erythema decreased on days 1 and 2 in the presence of 0.05% betamethasone valerate.
Bupivacaine castor oil Gel formulation Gel DM showed very slight or minimal oedema and erythema only at the injection site.
Table 14: skin reaction (edema) was produced after 0.5mL subcutaneous injection
Table 15: skin reaction (erythema) was produced after 0.5mL subcutaneous injection
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EXAMPLE 15 rat sciatic nerve block test
Male rats weighing 200-250 g were used for the test to evaluate the duration of nerve block for each of the different semi-solid formulations. Animals are kept daily for treatment of rats and the rats are placed in the experimental environment for more than one hour prior to testing. The sensory and motor nerve block test is as follows. In addition to sensory testing, motor function testing was performed at each time point to detect gait posture and foot lifting of the rat's hind legs. The handling and care of animals is in compliance with institutional, state and federal animal welfare regulations. Protocols were agreed by the laboratory animal administration committee (IACAC).
All rats were anesthetized with 3.5-4% isoflurane oxygen and then maintained under anesthesia with 1.5-2% isoflurane. Under aseptic conditions, the left leg area was shaved off and an incision was made at the upper 1/3 position. The thigh muscle was gently separated by blunt dissection to expose the sciatic nerve. Under direct vision, the semisolid gel formulation was injected into the vicinity of the sciatic nerve deep in the fascia plane and leg tendons. The outermost fascia layers are closed with a single suture. The incision sheath is closed with surgical staples and the outer skin edge is approximated. For all rats, the semi-solid formulation containing the drug was implanted on the left side of the sciatic nerve.
Hot plate experiment: at each time point, rats were placed on a hot plate at 56 ℃ and the time of delay (latency of lifting) of lifting the rear feet (for both feet of the animal) was recorded three times, at least 5 minutes apart. The cut-off time was set at 10 seconds to prevent hyperalgesia or injury. The average of 3 readings was taken as the final reading at a particular time point.
Recovery foot lifting ability (Paw playing) test: for both feet, the animals were gently held by a trained researcher and one dorsal foot was slowly slid over the edge of the test platform at a time until the toes were reached and repeated five times. Each time, the rat successfully placed its test foot on the platform surface, it scored a 1 (thus, the maximum score for each foot was 5), and if failed, a score of 0.
Recovery walking performance (Paw motor ability) test: recovery walking performance test animals were evaluated according to the following levels (casttillo, 1996,Anesthesiology 85:1157-66) using a scale of 1 to 4:
(1) Normal appearance;
(2) Complete dorsiflexion, but abnormal toe opening when the tail of the rat is raised;
(3) Complete plantarflexion, no splaying ability;
(4) Gait abnormalities occurred on a 3-point basis.
Recovery walking performance assessment is also used for each time point. For both feet, the back of the animal was held gently by a trained laboratory technician.
Dissecting: two weeks after administration, the skin at the surgical site was examined to see if wound healing was affected. The semi-solid formulation administration site was then re-opened under anesthesia and visually inspected. After the end of the experiment, the experimental rats were euthanized with carbon dioxide gas.
1. Therapeutic/analgesic effect for postoperative pain relief
The first day after surgery is very painful, requiring powerful analgesic effects to ensure pain relief and opioid sparing. If the product does not provide adequate analgesia on the first day, opioid use is required.
Ideally, bupivacaine semi-solid gel formulations provide (1) a sufficiently fast release to provide the desired analgesic effect for the first critical 24 hours following traumatic injury, (2) a sufficiently slow release to extend to a sustained effect of 72 hours, (3) a dose sufficient to release at the desired rate over an extended period of time, (4) a sufficiently small volume and a sufficiently low viscosity to facilitate administration, which has heretofore been difficult to achieve.
2. Bupivacaine castor oil gel formulation
The pharmacodynamic activity of bupivacaine released by the castor oil gel formulation resulted in a stronger analgesic effect when evaluated in the rat sciatic nerve block model than the pure castor oil bupivacaine oil formulation (figure 5). The hot plate delay versus time for the measurement of sensory function for bupivacaine castor oil gel formulations is shown in figure 5. The delayed response time of the left hind leg on a 56 ℃ hotplate was recorded to evaluate the effect of blocking the sensory nerve.
Bupivacaine castor oil solution formulations containing 8 wt% bupivacaine were used as control formulations. The solution of bupivacaine oil can produce a limited analgesic response in the rat sciatic nerve block model for about 4-6 hours due to its relatively high viscosity and relatively slow dissolution of bupivacaine free base into body fluids.
However, with the aid of the gelling agent, the ricinoleic acid-bicin gel formulation provides a powerful sensory and motor retardation effect within the first 24 hours, and prolonged partial retardation up to 72 hours, with the desired analgesic effect (moderate retardation on the second day, partial retardation on the third day, which matches the pain intensity conditions of severe pain on the first day, moderate pain on the second day, and only slight pain on the third day of typical surgical patients).
The recovery performance test measurement of bupivacaine castor oil gel formulations is shown in figure 6 as a function of time. The recovery walking exercise capacity test is classified into a class of 1 to 4, and the recovery walking exercise capacity of animals is evaluated.
The bupivacaine castor oil gel formulation group can produce a strong motion block within the first 24 hours and a prolonged partial block of up to 48 hours, matching the pain level of the surgical patient (fig. 6), whereas the bupivacaine castor oil solution formulation can produce only a strong motion block of 2 hours and a partial motion block of 6 hours. In order to provide effective analgesia, a strong motor block is required for the first 24 hours after a traumatic operation. All groups had reversible motor function and recovered to normal values 72 hours after dosing.
Surgical site wound healing and dissection:
two weeks after administration, the skin at the surgical site was examined to see if wound healing was affected. No adverse effect of the gel formulation on wound healing was observed and the surgical site healed well within about two weeks. Only slight oedema and erythema were observed with bupivacaine castor oil gel formulations following formulation administration.
The experimental rats were re-incised with surgical wounds under anesthesia and visually observed. The site of administration was pink, and sciatic nerve was observed normally, and no inflammation, necrosis, ulcer or infection was observed. In addition, most of the gel formulation was dissolved and absorbed, and only a small amount of residue was observed at the administration site.
3. Bupivacaine castor oil gel preparation with antiinflammatory effect
Inflammatory responses after acute injury, such as surgical incisions, result in post-operative inflammation, which impairs the ability of local anesthetics (including bupivacaine) to block sensory nerve conduction. The acidic environment created by the latter due to the inflammatory response prevents the analgesic from penetrating the nerve cell membrane. The pain level within 72 hours can be maximally reduced by incorporating an anti-inflammatory agent such as BET, betV, MP, keto or TA to produce bupivacaine castor oil gel formulations with anti-inflammatory effects to overcome the surgical inflammatory response.
The 72 hour observation shows that the bupivacaine castor oil gel formulation with anti-inflammatory effect enhances nerve blocking effect compared to bupivacaine castor oil gel formulation without anti-inflammatory effect.
The addition of the anti-inflammatory agent confirmed that the bupivacaine castor oil gel formulation having the anti-inflammatory effect had a stronger analgesic effect (increased strength) and a strong sensory and motor nerve block within the first 24 hours and a moderate partial blocking effect within 72 hours after the traumatic injury, compared to the bupivacaine castor oil gel formulation having no anti-inflammatory effect. Furthermore, bupivacaine castor oil gel formulations with anti-inflammatory effect even prolonged partial sensory retardation for 96 to 120 hours (figures 7 and 8). Therefore, the bupivacaine castor oil gel formulation having an anti-inflammatory effect can be used for treating postoperative pain of various different types of very painful surgery, such as middle/large abdominal surgery, gynecology, thoracic and plastic surgery, etc., expanding clinical practicality.
Stability of bupivacaine castor oil semisolid gel formulation
The bupivacaine castor oil gel formulations are stable to heat treatment and final autoclaving, as well as to various storage conditions at-5 ℃,4 ℃,25 ℃ and 40 ℃. After the completion of the preparation, the preparation was filled into a glass prefilled syringe, and the obtained formulation was sterilized using an autoclave (steam sterilization cycle 121 ℃ C..times.20 minutes). After preparation and steam sterilization, the total bupivacaine-related material content was about 0.10%. After one month of storage at 40 ℃, an additional 0.1% bupivacaine was degraded/oxidized. The bupivacaine castor oil gel formulation is expected to be stable at room temperature. Furthermore, no phase separation or precipitation or drug crystallization occurred during one month under all of the above storage conditions.

Claims (13)

1. A pharmaceutical formulation comprising:
(A) A glyceride mixture comprising: (i) Castor oil, and (ii) a solid glyceride having a melting point of between 37 and 75 ℃, preferably between 37 and 50 ℃, more preferably between 37 and 64 ℃; wherein the ratio of (i) to (ii) is from 10:1 to 6:3 (w/w); and
(B) An active material comprising: (i) Providing a therapeutically effective amount of bupivacaine for at least two days to relieve pain; and, optionally, (ii) a corticosteroid, an analgesic or an anti-inflammatory agent;
Wherein the active substance is dissolved in the glyceride mixture at a concentration of 0.01-60 wt%; the pharmaceutical formulation is a biocompatible, bioerodible, homogeneous, and monophasic semisolid gel; the viscosity of the pharmaceutical formulation is 50-2000cPs at 30 ℃.
2. The pharmaceutical formulation of claim 1, wherein the active substance comprises a corticosteroid, an analgesic, or an anti-inflammatory agent; preferably, the corticosteroid is a glucocorticoid; preferably, the anti-inflammatory agent is a non-steroidal anti-inflammatory agent selected from the group consisting of ketoprofen, naproxen, meloxicam, a COX-1 inhibitor and a COX-2 inhibitor.
3. The pharmaceutical formulation of claim 1, wherein the solid glyceride is selected from the group consisting of: a mixture of C12 to C18 triglycerides having a melting point of 42.5 ℃ to 46 ℃; a mixture of C12 to C18 triglycerides having a melting point of 42 ℃ to 45 ℃; a mixture of C12 to C18 triglycerides having a melting point of 37.8 ℃ to 39.8 ℃; triglycerides of C10 to C18 fatty acids having a melting point of 39 ℃ to 42 ℃; a C12 to C18 fatty acid having a melting point of 42 ℃ to 45 ℃; glyceryl monostearate having a melting point of 54 ℃ to 64 ℃; monoglyceride, diglyceride and triglyceride mixtures of C12 to C18 fatty acids having a melting point of 37 ℃ to 40 ℃; a mixture of triglycerides, diglycerides or monoglycerides having a melting point of 42 ℃ to 44 ℃; and a mixture of triglycerides, diglycerides or monoglycerides having a melting point of 37 ℃ to 39 ℃;
Preferably, the solid glyceride is selected from:DM、/>D、/>CM、/>378、GELUCIRE 43/01、GELEOL TM 、GELUCIRE 39/01、/>e85 ande76; more preferably, the solid glyceride is +.>DM。
4. A pharmaceutical formulation according to any one of claims 1 to 3, wherein the mass ratio of the glyceride mixture castor oil and solid glyceride is 8:1.0, 8:1.1, 8:1.2, 8:1.3, 8:1.4, 8:1.5, 8:1.6, 8:1.7, 8:1.8, 8:1.9, 8:2.0, 8:2.1, 8:2.2, 8:2.3, 8:2.4 or 8:2.5; preferably, the glyceride mixture comprises castor oil in a mass ratio of 8:1.0, 8:1.1, 8:1.2, 8:1.3, 8:1.4, 8:1.5, 8:1.6, 8:1.7, 8:1.8, 8:1.9, 8:2.0, 8:2.1, 8:2.2, 8:2.3, 8:2.4 or 8:2.5:DM。
5. a pharmaceutical formulation according to any one of claims 1-3, wherein less than 80%, preferably less than 60%, preferably less than 66% of bupivacaine is released from the reservoir of the semi-solid gel within 5 days when tested in vitro at 37 ℃.
6. A pharmaceutical formulation according to any one of claims 1 to 3, wherein the pharmaceutical formulation has a viscosity of less than 701cPs, or 50 to 1000cPs at 30 ℃.
7. A pharmaceutical formulation according to any one of claims 1-3, wherein the pharmaceutical formulation releases bupivacaine for at least one week, preferably at least two weeks, when tested in vitro at 37 ℃.
8. A pharmaceutical formulation according to any one of claims 1-3, wherein the glyceride mixture has a water solubility of less than 1mg/ml, preferably less than 0.1mg/ml, in a physiological pH buffer at 37 ℃.
9. A pharmaceutical formulation according to any one of claims 1-3, wherein the pharmaceutical formulation is for use in the treatment of post-operative pain.
10. A pharmaceutical formulation according to any one of claims 1-3, wherein a single injection of the pharmaceutical formulation comprises an amount of bupivacaine effective to provide a 72 hour sensory block.
11. A pharmaceutical formulation according to any one of claims 1-3, wherein a single injection of the pharmaceutical formulation causes a significant movement retardation.
12. The pharmaceutical formulation of claim 1, wherein the concentration of the active agent is 5-40 wt%; preferably, the concentration of the active substance is 5-20% by weight.
13. Pharmaceutical formulation according to claim 1, wherein the solid glycerides are present in an amount of 10 to 30 wt%, preferably 10 to 20 wt%, based on the total weight of castor oil and solid glycerides.
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